Imidazo[1,5-a][1,4]benzodiazepines

ABSTRACT

Compounds are disclosed of the formula ##STR1## wherein R 1  is hydrogen, halogen or trifluoromethyl; R 2  is selected from the group consisting of lower alkylthio together with the sulfoxide and sulfone thereof, halo, lower alkylamino or lower alkoxy; Y is oxo or thio; R 3  is selected from the group consisting of hydrogen, --COOR 4  wherein R 4  is hydrogen or lower alkyl, --CONR 6  R 5  wherein R 5  and R 6  are hydrogen or lower alkyl; X is hydrogen or halogen; and R 7  is lower alkyl or hydrogen and the pharmaceutically acceptable salts and N-oxides thereof. 
     Also presented are processes to produce the above compounds and intermediates therefor and derivatives thereof.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the formula ##STR2##wherein R₁ is hydrogen, halogen or trifluoromethyl; R₂ is selected fromthe group consisting of lower alkylthio together with the sulfoxide andsulfone thereof, halo, lower alkylamino or lower alkoxy; Y is oxo orthio; R₃ is selected from the group consisting of hydrogen, --COOR₄wherein R₄ is hydrogen or lower alkyl; --CONR₆ R₅ wherein R₅ and R₆ arehydrogen or lower alkyl; X is hydrogen or halogen; and R₇ is lower alkylor hydrogen

And the pharmaceutically acceptable salts and N-oxides thereof.

As used in this disclosure, the term "lower alkyl" or "alkyl"comprehends both straight and branched chain (C₁ to C₇) carbon-hydrogenradicals, preferably C₁ to C₄ carbon-hydrogen radicals such as methyl,ethyl, propyl, isopropyl, butyl and the like.

The term "halogen" is used to include all four forms thereof, i.e.,chlorine, bromine, fluorine and iodine,

The compounds of the present invention exhibit pharmacological activityas sedatives, muscle relaxants, anxiolytics and anticonvulsants.

The following reaction scheme sets forth the processes utilized toproduce the novel compounds of the present invention. ##STR3##

I → II

Compounds of the formula I are known in the prior art. Methods for theirpreparation are disclosed, for instance, in Belgian Pat. No. 833,248 ofMar. 10, 1976. The compound of formula I is reacted with phosgene in thepresence of an acid acceptor, such as an organic or inorganic base,e.g., pyridine, triethylamine, potassium carbonate or, preferably, ahydrogen chloride scavenger, such as 1,2-epoxy-3-phenoxypropane. Thereaction is effected at a temperature of between -50° C. to roomtemperature with 0° C. preferred. Solvents suitable for the reactioninclude aliphatic or aromatic hydrocarbons or chlorinated hydrocarbons,e.g., benzene, toluene, xylene, chlorobenzene or preferably methylenechloride ethers, e.g., THF.

I → III

Reaction of a compound of formula I with thiophosgene results in thethiocompound of formula III. The reaction parameters are as in Step III.

II → VI

The compound of formula II is alkylated by initial reaction with astrong base such as sodium methoxide, potassium-t-butoxide, sodiumhydride, etc. Thereafter a subsequent reaction with lower alkyl halide,e.g., methyl iodide or a dialkyl sulfate, e.g., dimethyl sulfate iscarried out in situ. Solvents suitable for such a reaction include loweralkanols (C₁ -C₄), ethers, DMF and DMSO. The reaction temperature may bevaried from -30° C. to 50° C. with room temperature preferred.

II, III or VI → IV or VII, respectively

The esters of formulas II or III may be hydrolyzed to the correspondingacids by reaction with an alkali metal hydroxide such as sodium orpotassium hydroxide in solvents such as C₁ to C₄ alcohols, ethers, DMSOor water or aqueous mixtures thereof. The reaction temperature is in therange of room temperature to reflux temperature with reflux temperatureof the selected solvent as preferred.

II or III → IX or V, respectively

The esters of formulas II or III may be converted directly to theprimary or secondary amides by reaction with ammonia or a loweralkylamine in an autoclave or sealed vessel under high pressure, i.e.,above atmospheric pressure. Solvents for such a reaction include C₁ -C₄alcohols, pyridine, DMSO, ethers or the alkylamines may be utilized assolvents themselves. The temperature of the reaction may be varied from100° C. to 150° C. with 130° C. as preferred.

VII or IV → IX or V, respectively

The acids of formulas VII or IV may also be converted to thecorresponding primary, secondary or tertiary amides by reaction of theparticular acid with an agent such as thionyl chloride or phosphoruspentachloride to form the acid chloride and thereafter converting theacid chloride to the amide by reaction with ammonia or lower alkylamine.Solvents for such a reaction include chlorinated hydrocarbons, such aschloroform or methylene chloride or aromatic hydrocarbons, such asbenzene or toluene. The reaction temperature may vary from -20° C. to50° C. with room temperature as preferred.

III → X

The ester of formula III is converted to the corresponding alkylthiocompound by reaction with an alkyl or dialkyl sulfate in the presence ofa strong base such as sodium methoxide, potassium-t-butoxide or sodiumhydride. Solvents suitable for such a reaction include C₁ -C₄ alcohols,ethers, DMF and DMSO. The reaction may vary between -30° C. to refluxtemperature of the selected solvent with room temperature preferred.

X → XI

The ester of formula X may be converted to the acid intermediate andthereafter converted to the primary, secondary or tertiary amide or Xmay be directly converted to the primary and secondary amide. Thereaction parameters (agent, solvents, temperature, etc.) are the same asthose for Steps II or III → VII or IV; II or III → IX or V' and VII orIV → IX or V above.

VII → VIII

The acid of formula VII may be decarboxylated to the compound of formulaVIII by pyrolysis, i.e., heating to between 160° C. to 250° C. with orwithout solvent present. Solvents which may be utilized includetrichlorobenzene, ethylene glycol or mineral oil.

X → XII(A) and XII(B)

The alkylthio compound of formula X may be oxidized to the sulfoxide andsulfone compounds XII(A and B) by treatment with hydrogen peroxide ororganic peracids such as meta-chloroperbenzoic acid. Solvents for such areaction include methylene chloride, chloroform or acetic acid. Thetemperature range for the reaction ranges from -20° C. to roomtemperature with 0° C. as most preferred although the variation oftemperature will determine the relative percentage of sulfoxide versussulfone as end product along with the amount of oxidizing agentutilized. The sulfone and sulfoxide compounds may be separated byfractional crystallization or by chromatographic methods known in theart.

II → XIII

Conversion of the oxo compound of formula II to the halogenated compoundis effected by reaction with phosphorus-oxyhalides, e.g.,phosphorus-oxybromide or phosphorus-oxychloride orphosphorus-pentachloride. Solvents for the reaction include hydrocarbonse.g., benzene or toluene, chlorinated hydrocarbons, e.g., methylenechloride or chlorobenzene or the reagents themselves can function assolvents. The temperature range of the reaction can vary from about 60°C. to reflux temperature of the selected solvent with reflux temperatureas preferred.

XIII → XV

The reaction of the ester compound of formula XIII to the primary,secondary or tertiary amide is effected by utilizing the reactionparameters (reagents, solvents, temperatures, etc.) as in Steps II orIII → VII or IV; II or III → IX or V; and VII or IV → IX or V above,i.e., directly or through the acid.

XIII → XVI

The halogen of the compound of formula XIII may be displaced with analkali metal alkoxide, e.g., sodium methoxide or potassium ethoxide. Thesolvent chosen for the reaction should represent the correspondingalcohol (C₁ -C₇) preferably (C₁ -C₄) or mixtures of inert solvents suchas ethers, DMF and DMSO. The reaction temperature ranges from about 60°C. to about 150° C. with about 120° C. as preferred.

XVI → XVII

The conversion of the ester of formula XVI to the amide follows thereaction parameters set forth in Steps II or III → VII or IV; II or III→ IX or V; and VII or IV → IX or V above; i.e., through the acid ordirectly from the ester.

XIII → XIV

The reaction of the ester compound of formula XIII to the primary orsecondary amide is effected by utilizing the reaction parameters as inStep XIII → XV except that the reaction conditions are more rigorous,i.e., at a higher temperature and longer reaction time, e.g., at orabove 120° C. with the reaction time prolonged, e.g., over 2 days.

It should be noted that where the ortho substituent on the phenyl moietyis fluorine, the vigorous direct animation step (ester to amide) ofsteps XIII → XIV or XVI would most probably also be accompanied bydisplacement of the fluorine by the amine or alkoxide.

XV → XVII

Compounds of the formula XV may thereafter be converted to compounds ofthe formula XVII by reaction with an alkali metal alkoxide, e.g., sodiummethoxide or potassium ethoxide. The reaction parameters are as in StepXIII → XVI.

An additional reaction scheme to produce compounds of the presentinvention is as follows: ##STR4##

I → XXIV

The compound of formula I may be reacted with lower alkyl haloformates,such as, ethylchloroformate, which may be generated in situ by reactionof phosgene and ethanol to give the compounds of formula XXIV. Otherreaction parameters are as in Step I → II.

XXIV → II

The compound of formula XXIV is thereafter cyclized by treatment withstrong base such as sodium methoxide, potassium-t-butoxide, sodiumhydride, etc. Solvents for the reaction include DMF, THF and DMSO. Thereaction temperature ranges from about 80° C. to about 150° C. withabout 100° C. as preferred.

Yet another reaction scheme to produce the compounds of the presentinvention is as follows: ##STR5##

XVIII → XIX

The compound of formula XVIII is known in the art and a method for itspreparation has been disclosed in Belgian Pat. No. 833,248 issued Mar.10, 1976. The compound of formula XVIII may be reacted with phosgene (ifthe oxo analog is desired) or with thiophosgene to produce thethio-compound of formula XIX. The reaction parameters, i.e., thereagents, solvents, reaction temperatures, etc., are as described inSteps I → II or in this instance I → III.

XIX → XX

The compound of formula XIX is thereafter alkylated by initial reactionwith a strong base such as sodium hydroxide, sodium methoxide, sodiumhydride, etc. Thereafter, a subsequent reaction with a dialkyl sulfate,e.g., dimethylsulfate or a lower alkyl halide, e.g., methyl iodide iscarried out in situ. Solvents for such a reaction include lower (C₁ -C₄)alcohols, ethers, DMF and DMSO. The reaction temperature may be variedfrom about -30° C. to about 50° C. with room temperature preferred.

XX → XXI

The compound of formula XX is thereafter oxidized to the unsaturatedcompound by reaction with manganese dioxide in an inert hydrocarbon,e.g., benzene, toluene, etc., or chlorinated hydrocarbons, e.g.,chlorobenzene. The temperature of the reaction may vary from about 80°C. to 150° C. with reflux temperature of the solvent being preferred.

XXI → XXII or XXIII

The compound of formula XXI may thereafter be oxidized to the sulfoxide(XXII) or the sulfone-N-oxide (XXIII) by reaction with hydrogen peroxideor an organic peracid, such as perbenzoic acid or peracetic acid.Solvents for such a reaction include acetic acid or chlorinatedhydrocarbons, such as chlorobenzene or methylene chloride. Thetemperature may range from -20° C. to 100° C. with room temperaturebeing preferred for production of the sulfoxide (XXII). Thesulfone-N-oxide is produced by utilizing an excess of reagent, i.e.,hydrogen peroxide or peracid and by using increased temperature, i.e.,50° C. to 100° C. being preferred. Increase of reaction time will alsobring about the predominance of the N-oxide (XXIII).

The compounds of the present invention exhibit pharmacological activityas anxiolytics, sedatives, muscle relaxants and anticonvulsants. Ascontemplated by this invention, the novel compounds of the presentinvention and their pharmaceutically acceptable salts can be embodied inpharmaceutical dosage formulations containing from about 0.1 to about200 mg., most preferably 1-100 mg., with the dosage adjusted to speciesand individual patient requirements. The novel compounds and theirpharmaceutically acceptable salts can be administered internally, forexample, parenterally or enterally, in conventional pharmaceuticaldosage forms. For example, they can be incorporated in conventionalliquid or solid vehicles such as water, gelatin, starch, magnesiumstearate, talc, vegetable oils and the like to provide tablets, elixirs,capsules, solutions, emulsions and the like according to acceptablepharmaceutical practices.

The expression "pharmaceutically acceptable salts" is used to includeboth inorganic and organic pharmaceutically acceptable acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,succinic acid, tartaric acid, methanesulfonic acid, paratoluenesulfonicacid and the like. Such salts can be formed quite readily by thoseskilled in the art, with the prior art and the nature of the compound tobe placed in salt form, in view.

A preferred genus are compounds of the formula ##STR6## wherein X ishydrogen, chloro or fluoro; R₂ is --O--alkyl, chloro, --S--alkyl orNHCH₃ ; R₃ is CONH₂, ##STR7##

EXAMPLE 1[7-Chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-ylidene]-alpha-(ethoxycarbonylamino)aceticacid, methyl ester

A solution of 7.5 g (0.02 mole) of7-chloro-5-(2-fluorophenyl)-α-hydroxyimino-3H-1,4-benzodiazepine-2-aceticacid, methyl ester in 150 ml of dimethylformamide and 50 ml of ethanolwas hydrogenated over Raney nickel (1 teaspoonful) at atmosphericpressure for 21/2 hours. The catalyst was filtered and 10 ml of pyridinewas added to the filtrate. After cooling to -20°, 30 ml of a 10%solution of phosgene in benzene was added with stirring. The reactionmixture was allowed to reach room temperature and was then evaporatedunder reduced pressure to dryness. The residue was partitioned betweenmethylene chloride and saturated sodium bicarbonate solution. Theorganic phase was dried and evaporated. The residue was chromatographedover 300 g of silica gel using 20% (v/v) of ethyl acetate in methylenechloride. Crystallization of the combined clean fractions from etheryielded yellowish crystals. The analytical sample was recrystallizedfrom methylene chloride/ethyl acetate/hexane and gave off-white crystalswith mp 188°-191°. Uv λ infl. 242 mμ (ε=20800) infl 275 (10500) max 313(30800) infl ca 365 (3400) ir (CHCl₃) 3400 cm⁻¹, 3250, 3200 (NH) 1720(COOEt) 1665 (COOCH₃) 1620; nmr (CDCl₃) δ 1.25 (t, 3, J=7 Hz, --CH₂ CH₃)3.72 (s, 3, OCH₃) 4.13 (q, 2, J=7 Hz, --OCH₂ --) 4.43 (broad s, 2, --CH₂--) 5.83 (s, 1, NH) 6.8-7.8 (m, 7, aromatic H) 11.0 (s, 1, NH).

Anal. Calcd. for C₂₁ H₁₉ ClFN₃ O₄ : C, 58.41; H, 4.43; N, 9.73. Found:C, 58.32; H, 4.39; N, 9.72.

EXAMPLE 28-Chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester

A stirred solution of 15 g (0.04 mole) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepineand 12 g (0.08 mole) of 1,2-epoxy-3-phenoxypropane in 150 ml ofmethylene chloride was cooled in an ice-salt bath and treated with 47 g(0.06 mole) of a 12.5% solution of phosgene in benzene at a moderaterate. Stirring in the cold under a drying tube was continued for 2hours. A cold solution of 3N ammonium hydroxide (50 ml) was added andstirring was continued for 10 min. The organic phase was separated,dried over sodium sulfate and evaporated under reduced pressure.Stirring the oily residue with anhydrous ether gave off-white crystals.The crystals were filtered, washed with ether and air dried on thefunnel to yield the end product. Recrystallization from ethanolmethylene chloride gave white needles with mp 273°-276° (dec). Uv λ max223 mμ (ε=43800) 276 (21100) infl 348 (1100) ir (KBr) 3150 (NH) 1720(COOMe, CO) nmr (CDCl₃) δ 3.80 ppm (s, 3, OCH₃) 4.11 (broad d, 1) and5.58 (broad d, 1) (AB-system, J=12 Hz, C₄ -H) 6.95 (d, 1, J=2.5 Hz, C₇-H) 7.3-7.8 (m, 5, aromatic H) 7.96 (d, 1, J=8 Hz, C₁₀ -H) 11.19 (broads, 1, NH).

Anal. Calcd. for C₁₉ H₁₃ Cl₂ N₃ O₃ : C, 56.74; H, 3.26; N, 10.45. Found:C, 56.89; H, 3.43; N, 10.35.

EXAMPLE 38-Chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester, and8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-6H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylicacid, methyl ester

Potassium t-butoxide, 1.2 g (0.0107 mole), was added to a solution of4.32 g (0.01 mole) of[7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-ylidene[-.alpha.-(ethoxycarbonylamino)acetic acid methyl ester in 50 ml of dry dimethylformamide. The reactionmixture was stirred under nitrogen and slowly heated up to 115°-120°,then cooled, acidified by addition of 1 ml of glacial acetic acid andpartitioned between methylene chloride and saturated sodium bicarbonatesolution. The organic phase was washed with water, dried and evaporated.Crystallization of the residue from ethyl acetate yielded a mixture ofthe two isomeric products which were separated by chromatography over250 g of silica gel using methylene chloride/ethyl acetate 2:1. The lesspolar component (6H) was crystallized from methylene chloride/ether togive colorless crystals which were recrystallized fromtetrahydrofuran/ethanol for analysis, mp 262°-264°. Uv λ infl 240 mμ(ε-7900) infl 255 (6600) max 261 (7100) 267 (7000) infl 280 (5200) max331 (13250) ir (KBr) 1720 cm⁻¹ (COOCH₃); nmr (d-DMSO) δ 3.83 (s, 3,OCH₃) 5.95 (d, 1, J=2 Hz, C₆ -H) 6.5 (s, 1, J=2 Hz, C₇ -H) 7.0-8.3 (m.6, aromatic H) 8.55 (d, 1, J=2 Hz, C₄ -H) 11.9 (broad s, 1, NH).

Anal. Calcd. for C₁₉ H₁₃ ClFN₃ O₃ : C, 59.16; H, 3.40; N, 10.89. Found:C, 59.12; H, 3.33; N, 10.67.

The more polar major component was crystallized from methylenechloride/ethyl acetate to yield the 4H compound with mp 252°-254°. Uv λin fl 213 mμ (ε=34000) max 278 (21450) infl 285 (20700); ir (KBr) 1720cm⁻¹, 1705 (COOCH₃, CO) nmr (CDCl₃) δ 3.8 ppm (s, 3, OCH₃) 4.1 (d, 1)and 5.56 (d,1) (AB-system), J=12.5 Hz, C₄ -H) 7.7.8 (m, 5, aromatic H)7.97 (d, 1, J=8 Hz, C₁₀ -H) 11.25 (broad s, 1, NH).

Anal. Calcd. for C₁₉ H₁₃ ClFN₃ O₃ : C, 59.15; H, 3.40; N, 10.89. Found:C, 59.22; H, 3.24; N, 11.05.

EXAMPLE 48-Chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-thione-3-carboxylicacid, methyl ester

A stirred solution of 15 g (0.04 mole) of2-[(amino)methoxycarbonylmethylene]-7-chloro-5-(2-chlorophenyl-1,3-dihydro-2H-1,4-benzodiazepineand of 12 g (0.08 mole) of 1,2-epoxy-3-phenoxypropane in 80 ml ofmethylene chloride was cooled in an ice-salt bath and treated rapidlywith a solution of thiophosgene (7 g, 0.06 mole) in 70 ml of methylenechloride. Stirring in the cold under a drying tube was continued for 2hours. Cold 3N ammonium hydroxide solution (50 ml) was added andstirring in the cold was continued for an additional 30 min. The organiclayer was washed with 6N hydrochloric acid, dried over sodium sulfateand evaporated. The oily residue was stirred with ether to give a lighttan solid with mp ca. 230°. Recrystallization from ethanol/methylenechloride gave light tan plates with mp 232°-235°. Uv λ max 220 mμ(ε=55500) 297 (14300) ir (KBr) 1720 cm⁻¹ ; nmr (d-DMSO) δ 3.84 ppm (s,3, OCH₃) 4.05 (d, 1) and 5.59 (d, 1) (AB-system, J=12 Hz, C₄ -H) 7.01(d, 1, J=2.5 Hz, C₇ -H) 7.3-7.8 (m, 5, aromatic H) 8.39 (d, 1, J=8 Hz,C₁₀ -H) 13.28 (broad s, 1, NH).

Anal. Calcd. for C₁₉ H₁₃ Cl₂ N₃ O₂ S: C, 54.56; H, 3.13; N, 10.05.Found: C, 54.78; H, 3.46; N, 10.12.

EXAMPLE 58-Chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-thione-3-carboxylicacid

A solution of 1.1 g (0.02 mole) of potassium hydroxide in 40 ml ofmethanol was treated with 2.1 g (0.005 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-thione-3-carboxylicacid methyl ester in a beaker. The solution was boiled in a steambathfor 15 min and then evaporated at reduced pressure at 50°-60°. Anaqueous solution of the residue was acidified with cold 6N aqueoushydrochloric acid adding ice to keep the mixture cold. The solid wascollected by filtration, washed with water and air dried on the funnelovernight to yield crude end product. Recrystallization from ethanolgave light tan crystals with mp 277°-280° (dec).

Anal. Calcd. for C₁₈ H₁₁ Cl₂ N₃ O₂ S: C, 53.48; H, 2.74; N, 10.39.Found: C, 53.55; H, 2.92; N, 10.39.

EXAMPLE 68-Chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-one

A mixture of 4.02 g (0.01 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester, 150 ml of methanol, 15 ml of water and 2 g (0.035mole) of potassium hydroxide was heated to reflux for 5 hours under anitrogen atmosphere. The solution was then concentrated down to 40 ml,acidified by addition of 4 ml of glacial acetic acid and crystallized bydiluting with water. The precipitate was collected, dried andrecrystallized from tetrahydrofuran/methanol/ethyl acetate to yield8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid which was decarboxylated as follows: A solution of 1 g of this acidin 5 ml of ethylene glycol was heated to reflux for 45 min and thenpartitioned between methylene chloride and saturated sodium bicarbonatesolution. The organic layer was washed with bicarbonate solution andwater, dried and evaporated. Crystallization of the residue from ethylacetate/ether gave end product which was further purified bychromatography over 20 g silica gel using methylene chloride/ethylacetate 1:3. Crystallization from ethyl acetate/ether yielded the purecolorless product with mp 236°-238°. nmr (CDCl₃) δ 4.15 ppm (broad d, 1)and 4.86 (broad d, 1) (AB-system, J= 13 Hz, C₄ -H) 6.25 (d, 1, J=2 Hz,C₃ -H) 6.98 (d, 1, J=2.5 Hz, C₇ -H) 7.1-7.7 (m, 5, aromatic H) 8.0 (d,1, J=8 Hz, C₁₀ -H) 10.4 (broad s, 1, NH).

Anal. Calcd. for C₁₇ H₁₁ Cl₂ N₃ O: C, 59.32; H, 3.22; N, 12.21. Found:C, 59.41; H, 3.23; N, 12.19.

EXAMPLE 78-Chloro-6-(2-fluorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-one

A mixture of 0.386 g (1 mmole) of8-chloro-1,2-dihydro-6-(2-fluorophenyl)-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester, 10 ml of methanol, 1 ml of water and 0.225 g (4mmole) of potassium hydroxide was heated to reflux for 31/2 hours underan atmosphere of nitrogen. The solvent was evaporated and the residuewas acidified with acetic acid and extracted with methylene chloride.The extracts were dried and evaporated and the residue was heated inmineral oil up to 230° for 5 min. The reaction mixture was partitionedbetween 1N hydrochloric acid and methylene chloride/hexane. The acidextract was made alkaline with sodium carbonate solution and extractedwith methylene chloride. The residue obtained after evaporation of thedried extracts was chromatographed over 10 g of silica gel usingmethylene chloride/ethyl acetate 1:2. Crystallization of the combinedclean fractions from ethyl acetate/hexane yielded colorless crystalswith mp 247°-250°. Uv λ max 212 mμ (ε=42250) sh 262 (10000) ir (KBr)1695 cm⁻¹ (CO) 3150 (NH). Nmr (CDCl₃) 4.18 ppm (d, 1) and 4.88 (d, 1)(AB-system, J=12.5 Hz, C₄ -H) 6.28 (d, 1, J=2 Hz, C₃ -H) 6.9-7.7 (m, 5,aromatic H) 8.13 (d, 1, J=8.5 Hz, C₁₀ -H) 10.46 (broad s, 1, NH).

Anal. Calcd. for C₁₇ H₁₁ ClFN₃ O: C, 62.30; H, 3.38; N, 12.82. Found: C,62.22; H, 3.33; N, 12.82.

EXAMPLE 88-Chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester ethanolate

A mixture of 1.1 g (0.02 mole) of sodium methylate and 4 g (0.01 mole)of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester in 100 ml of methanol was stirred under a drying tubefor 30 min. The resulting pale yellow solution was treated with 5 ml ofmethyl iodide and stirred 5 hrs longer at room temperature. Afteracidifying with acetic acid, the mixture was evaporated to dryness. Thebrown residue was partitioned between methylene chloride and water andthe organic phase was separated, dried and evaporated to give a tanfoam. Stirring the residue with 25 ml of ethanol gave a light tan solid.The solid was filtered, washed with a little ethanol and then withpetroleum ether. Air drying on the funnel gave end product with mp ca.120°. Recrystallization from ethanol gave off-white plates with mp120°-125° (dec) which contained 1 mole of ethanol according to theanalytical and spectral data. Uv λ sh 212 mμ (ε=41000) max 281 (19800)ir (CHCl₃) 1700 cm⁻¹ (CO) 1720 (COOCH₃) nmr (CDCl₃) δ 3.60 ppm (s, 3,NCH₃) 3.90 (s, 3, OCH₃) 4.07 (d, 1) and 5.83 (d, 1) (AB-system, J=12 Hz,C₄ -H) 7.05 (d, 1, J=2.5 Hz, C₇ -H). 7.2-7.8 (m, 5, aromatic H) 8.03 (d,1, J=8 Hz, C₁₀ -H).

Anal. Calcd. for C₂₀ H₁₅ Cl₂ N₃ O₃ C₂ H₅ OH: C, 57.15; H, 4.58; N, 9.09.Found: C, 57.14; H, 4.73; N, 9.16.

EXAMPLE 98-Chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid

Potassium hydroxide, 1.3 g (0.02 mole), was dissolved in 1 ml of waterand added to a suspension of 4 g (0.0097 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid methyl ester ethanolate in200 ml of methanol. The solution was refluxed under argon for 3 hrs,concentrated at reduced pressure, diluted with cold water and acidifiedwith acetic acid to give an off-white solid. The solid was washed withwater and air dried on the funnel overnight to give crude end product.Recrystallization from ethanol/methylene chloride gave white crystalswith mp 265°-267° (dec).

Anal. Calcd. for C₁₉ H₁₃ Cl₂ N₃ O₃ : C, 56.74; H, 3.25; N, 10.45. Found:C, 56.50; H, 3.37; N, 10.35.

EXAMPLE 108-Chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxamide

A stirred suspension of 3 g (0.0075 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylicacid in 90 ml of methylene chloride was cooled in an ice bath andtreated with 1.9 g (0.009 mole) of phosphorus pentachloride in portions.Stirring in the cold under a drying tube was continued for 30 min.Ammonia was then bubbled into the cold solution for 5 min and stirringin the cold was continued 30 min. longer. Evaporation at reducedpressure gave a tan solid. The solid was stirred with 3N ammoniumhydroxide and extracted with methylene chloride. An emulsion formed butwas destroyed by filtering to remove some high melting solid. Themethylene chloride layer was dried over sodium sulfate and evaporated togive a yellow solid which was recrystallized from benzene to giveoff-white needles with mp 158°-160°. Uv λ sh 215 mμ (ε=43000) max 272(15500) sh 330 (2500); ir (CHCl₃); ir (CHCl₃) 3510, 3400 cm⁻¹ (NH₂) 1703(CO) 1685 (CONH₂).

Anal. Calcd. for C₁₉ H₁₄ Cl₂ N₄ O₂ : C, 56.88; H, 3.52; N, 13.96. Found:C, 56.66; H, 3.70; N, 13.78.

EXAMPLE 118-Chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic,methyl ester

A stirred suspension of 10 g (0.024 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-1-thione-3-carboxylicacid methyl ester in 200 ml of methanol was cooled in an ice-salt bathunder argon and treated with 1.25 g (0.024 mole) of sodium methylate.The argon inlet tube was replaced by a drying tube and stirring in thecold was continued for 30 min. Methyl iodide, 6 ml or 14 g (0.1 mole)was added and stirring in the cold was continued for 2 hrs. The solutionwas poured into cold water to give a light tan solid. The solid wasfiltered, washed with water and air dried on the funnel to yield crudeend product. Trituration of the solid with boiling ether gave light tanprisms with mp 208°-211°. Recrystallization from ethanol gave paleyellow prisms with mp 209°-211°. Uv λ max 216 mμ (ε=50300) infl 245(22,300) sh 270 (14,000); ir (CHCl₃) 1728, 1717 cm⁻¹ (COOCH₃), nmr(CDCl₃) δ 2.66 ppm (s, 3, SCH₃) 3.88 (s, 3, OCH₃) 3.97 (d, 1) and 5.97(d, 1) (AB-system, J=12.5 Hz, C₄ -H) 7-7.8 (m, 7, aromatic H).

Anal. Calcd. for C₂₀ H₁₅ Cl₂ N₃ O₂ S: C, 55.57; H, 3.50; N, 9.72. Found:C, 55.65; H, 3.65; N, 9.77.

EXAMPLE 128-Chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 3 g (0.007 mole) of8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester and 60 ml of 25% solution of ammonia in methanol washeated at 130° in a steel bomb for 18 hrs. The contents of the bomb wereevaporated at reduced pressure to give light tan crystals, which wererecrystallized from methanol/methylene chloride to yield light tanprisms with mp 270°-274° (dec.). Uv λ max 217 mμ (ε=47,200) infl 242(23,200) sh 270 (11,500), ir (KBr) 3365, 3250, 3215, 3150 cm⁻¹ (NH₂)1675, 1650, 1590 (CON).

Anal. Calcd. for C₁₉ H₁₄ Cl₂ N₄ OS: C, 54.69; H, 3.38; N, 13.43. Found:C, 54.69; H, 3.34; N, 13.50.

EXAMPLE 13 8-Chloro-6-(2-chlorophenyl)-N-methyl-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 2.1 g (0.005 mole) of8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester and 20 ml of a 28% solution of methylamine in ethanolwas heated at 130° in a steel bomb for 18 hrs. The contents of the bombwere evaporated at reduced pressure to give a tan solid.Recrystallization from ethanol gave off-white prisms with mp 224°-227°.Uv λ max 218 mμ (ε=51,400) infl 245 (26,000) sh 275 (12,000); ir (KBr)3410 cm⁻¹ (NH) 1668, 1527 (CON).

Anal. Calcd. for C₂₀ H₁₆ Cl₂ N₄ OS: C, 55.69; H, 3.74; N, 12.99. Found:C, 55.63; H, 3.89; N, 12.99.

EXAMPLE 146-(2-Chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester

A stirred mixture of 10 g (0.025 mole) of8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester, 1 g (0.005 mole) of phosphorus pentachloride and 250ml of phosphorus oxychloride was refluxed under a drying tube for 44hrs. Benzene (250 ml) was added and the dark solution was evaporated invacuo at 50°-60°. Another 250 ml of benzene was added and the solutionwas again evaporated to dryness at reduced pressure. The residue wasdissolved in 250 ml of methylene chloride and cooled in an ice bath.Ammonia was bubbled into the cold solution for 5 min to give a tansolid. Stirring at room temperature was continued for 15 min. Themixture was filtered and evaporated at reduced pressure to give a browngum which solidified when triturated with 75 ml of boiling ether. Thissolid was dissolved in about 50 ml of methylene chloride and filteredover neutral alumina. Eluted first with methylene chloride and then with30% ethyl acetate in methylene chloride. Evaporation of the ethylacetate methylene chloride fractions gave a tan solid which wasrecrystallized from ethyl acetate to give off-white prisms with mp200°-202°. Uv λ sh 213 mμ (ε=44,600) infl 240 (27,500) infl 260 (20,000)infl 300 (1850) ir (CHCl₃) 1717 cm⁻¹ (COOCH₃) .

Anal. Calcd. for C₁₉ H₁₂ Cl₃ N₃ O₃ : C, 54.25; H, 2.88; N, 9.99. Found:C, 54.18; H, 3.10; N, 10.20.

EXAMPLE 156-(2-Chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid

A solution of 2 g (0.005 mole) of6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester 0.7 g (0.012 mole) of potassium hydroxide, 60 ml ofmethanol and 2 ml of water was refluxed under argon for 2.5 hrs. Thesolution was evaporated in vacuo at 50°-60°. An aqueous solution of theresidue was acidified with acetic acid to give a gelatinous, whiteprecipitate. The precipitate was collected by filtration, washed withwater and air dried on the funnel overnight to give off-white solid.Recrystallization from a solution of ethanol and methylene chloride gavewhite plates with mp 250°-253° (dec).

Anal. Calcd. for C₁₈ H₁₀ Cl₃ N₃ O₂ : C, 53.17; H, 2.48; N, 10.33. Found:C, 53.17; H, 2.46; N, 10.21.

EXAMPLE 168-Chloro-6-(2-chlorophenyl)-1-methylsulfinyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester and8-Chloro-6-(2-chlorophenyl)-1-methylsulfonyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester

A stirred solution of 3 g (0.007 mole) of8-chloro-6-(2-chlorophenyl)-1-methylthio-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester in 60 ml of methylene chloride was cooled in anice-salt bath and treated with 2.5 g (0.015 mole) of m-chloroperbenzoicacid in portions. Stirring in the cold was continued for 2 hrs under adrying tube. The mixture was washed with dilute ammonium hydroxidesolution, dried over sodium sulfate and evaporated to give an off-whitefoam which solidified when triturated with boiling ether. This materialwas chromatographed over silica gel using 20% (v/v) of ethyl acetate inmethylene chloride as eluent. The fractions containing the less polarcomponent were combined and evaporated. Crystallization fromethanol/methylene chloride yielded the sulfone with mp 220°-223°. Uv λmax 221 mμ (ε=41,800) infl 240 (32,000) infl 260 (18,500) infl 300(1500); ir (KBr) 1720 cm⁻¹ (COOCH₃) 1325, 1225 (SO₂).

Anal. Calcd. for C₂₀ H₁₅ Cl₂ N₃ O₄ S: C, 51.74; H, 3.26; N, 9.05. Found:C, 51.95; H, 3.41; N, 8.88.

The fractions containing the more polar major component were evaporatedand the residue was crystallized from ethanol/methylene chloride to givethe sulfoxide as white prisms with mp 223°-226°. Uv λ max 220 mμ(ε=41,000) infl 260 (12,500) infl 300 (1800); ir (KBr) 1718 cm⁻¹(COOCH₃) 1090 (SO).

Anal. Calcd. for C₂₀ H₁₅ Cl₂ N₃ O₃ S: C, 53.58; H, 3.37; N, 9.37. Found:C, 53.57; H, 3.52; N, 9.18.

EXAMPLE 178-Chloro-6-(2-chlorophenyl)-1-methoxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester

A mixture of 2.9 g (0.007 mole) of6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester, 1.1 g (0.02 mole) of sodium methoxide and 100 ml ofdry methanol was heated in a steel bomb at 115°-120° for 20 hrs. Thesolvent was removed at reduced pressure. The residue was dissolved inmethylene chloride, washed with dilute hydrochloric acid to give paleyellow amorphous solid. An ethereal solution (60 ml) of the solid waswashed with dilute ammonium hydroxide solution, dried, filtered andconcentrated on a steam bath to about 20 ml. White crystals wereobtained after keeping the solution at room temperature for severalhours with occasional scratching. Recrystallization from ether gavewhite crystals with mp 155°-160°. Uv λ sh 213 mμ (ε=36,000) max 266(20,500) ir (CHCl₃) 1715 cm⁻¹ (COOCH₃); nmr (CDCl₃) δ 3.93 ppm (s, 3,COOCH₃) 4.23 (s, 3, OCH₃) 4.08 (d, 1) and 6.06 (d, 1) AB-system, J=12Hz, C₄ -H) 7.1-7.9 (m, 7, aromatic H).

Anal. Calcd. for C₂₀ H₁₅ Cl₂ N₃ O₃ : C, 57.71; H, 3.63; N, 10.09. Found:C, 57.72; H, 3.57; N, 10.02.

EXAMPLE 188-Chloro-6-(2-chlorophenyl)-1-methoxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 0.3 g (0.00074 mole) of6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide,1.15 g (0.0028 mole) of sodium methoxide and 15 ml of methanol washeated at 120°-125° in a steel bomb for 24 hrs. The solvent wasevaporated in vacuo. The residue was dissolved in methylene chloride,washed with water, dried and evaporated at reduced pressure to give atan, amorphous solid. After chromatography over silica gel using 5%(v/v) of ethanol in methylene chloride the solid was recrystallized froma solution of ethanol and methylene chloride to give off-white crystalswith mp 235°-238° (dec). Uv λ max 216 l mμ (ε=41,000) sh 243 (22,600)max 264 (20,000); ir (KBr) 3445, 3330, 3280 cm⁻¹ (NH₂) 1675 (CON) nmr(d-DMSO) δ 4.0 ppm (d, 1) and 5.88 (d, 1) (AB-system, J=12 Hz, C₄ -H)4.06 (s, 3, OCH₃) 6.9-7.9 (m, 9, aromatic H and NH₂).

Anal. Calcd. for C₁₉ H₁₄ Cl₂ N₄ O₂ : C, 56.87; H, 3.52; N, 13.96. Found:C, 56.85; H, 3.41; N, 13.71.

EXAMPLE 196-(2-Chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 0.5 g (0.0012 mole) of6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester and 20 ml of a 20% solution of ammonia in methanol washeated at 120°-125° in a steel bomb for 18 hrs. Evaporation of thesolvent at reduced pressure gave an amorphous solid. The solid wasdissolved in methylene chloride, washed with water, dried and evaporatedat reduced pressure to give a tan, amorphous solid which crystallizedwhen stirred with a small amount of boiling ether. Recrystallizationfrom a solution of methanol and methylene chloride gave white crystalswith mp 285°-288°. Uv λ 214 mμ (ε=44,300) sh 245 (26,500) sh 260(16,400) sh 300 (600); ir (KBr) 3470, 3335 cm⁻¹ (NH₂) 1670 (CON).

Anal. Calcd. for C₁₈ H₁₁ Cl₃ N₄ O: C, 53.29; H, 2.73; N, 13.81. Found:C, 53.34; H, 2.77; N, 13.75.

EXAMPLE 206-(2-Chlorophenyl-1,8-dichloro-N-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamideand8-chloro-6-(2-chlorophenyl)-1-methylamino-N-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide

A mixture of 2.4 g (0.0056 mole) of6-(2-chlorophenyl)-1,8-dichloro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester and 80 ml of a 21% solution of methylamine in ethanolwas heated in a steel bomb at 120°-130° for 64 hrs. Evaporation of thesolution at reduced pressure gave a gum which was dissolved in methylenechloride. The solution was washed with water, dried and evaporated. Theresidue was chromatographed over 70 g of silica gel using 5% (v/v) oftetrahydrofuran in ethyl acetate as eluant. The fractions containing theless polar component were combined and evaporated. Crystallization frommethylene chloride/ethyl acetate gave the dichloro product which wasrecrystallized from ethanol/methylene chloride for analysis to givewhite prisms with mp 225°-228°. Uv λ max 216 mμ (ε=43,800) sh 240(28,600) sh 260 (17,000) sh 303 (1050) ir (CHCl₃) 3435 cm⁻¹ (NH) 1675(CON); nmr (CDCl₃) δ 2.97 (d, 3, J=5 Hz, NHCH₃) 4.0 (d, 1) and 6.26(d, 1) (AB-system, J=12.5 Hz, C₄ -H) 6.8-7.9 (m, 8, aromatic H and NH).

Anal. Calcd. for C₁₉ H₁₃ Cl₃ N₄ O: C, 54.38; H, 3.12; N, 13.35. Found:C, 54.39; H, 3.07; N, 13.43.

Evaporation and crystallization of the later fractions containing themore polar component yielded the monochloro product. Recrystallizationfrom ether/methanol gave off-white crystals with mp 208°-210°. Uv λ sh215 mμ (ε=42,600) sh 245 (17,300) max 274 (10,400) sh 293 (7600); ir(CHCl₃) 3425 cm⁻¹ (NH) 1655 (CON); nmr (CDCl₃) δ 2.90 (d, 3, J=5 Hz,NHCH₃) 3.97 (d, 3, J=5 Hz, NHCH₃)3.97 (d, 1) and 6.13 (d, 1) (AB-system,J=12.5 Hz, C₄ -H) 4.08 (q, 1, J=5 Hz, --NHCH₃) 6.8-7.8 (m, 8, aromatic Hand CONH).

Anal. Calcd. for C₂₀ H₁₇ Cl₂ N₅ O: C, 57.98; H,4.14; N, 16.90. Found: C,57.99; H, 4.26; N, 16.90.

EXAMPLE 21

Compounds of Example 3 may be alternately prepared by reaction of7-chloro-5-(2-fluorophenyl)-2-[(amino)methoxycarbonylmethylene]-1,3-dihydro-2H-1,4-benzodiazepinewith phosgene as described in Example 2.

EXAMPLE 228-Chloro-6-(2-fluorophenyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-a][1,4]benzodiazepin-1-one

A solution of 5 g (.0165 mole) of2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinein 100 ml of methylene chloride was stirred and cooled in a dryice-acetone bath. To this solution, 22.7 ml (.02 mole) of a 10-12%solution of phosgene in benzene was added, followed by 2 ml of pyridine.The mixture was stirred for 10 minutes on the cooling bath and then for10 minutes after removal of the bath. A saturated solution of sodiumbicarbonate, 250 ml., was added and stirring was continued for another10 minutes. The methylene chloride layer was separated, dried andevaporated to yield an oil. This oil was chromatographed over 100 g ofsilica gel (Merck, 70-230 mesh) using 10% (v/v) of ethanol in methylenechloride. Fractions containing product were combined and evaporated togive oil, which upon crystallization from ether yielded crystals with mp178°-180°. Recrystallization for analysis from methylene chloride/ethylacetate gave colorless crystals with mp 181°-183°.

Anal. Calcd. for C₁₇ H₁₃ ClFN₃ O: C, 61.92; H, 3.97; N, 12.74. Found: C,61.87; H, 4.01; N, 12.65. Uv (2-PrOH) λ infl 240 mμ (ε=19000) infl 270(4700) infl 315 (1000) IR (CHCl₃) 3450, 3250 cm⁻¹ (NH) 1710 (CO) NMR(CDCl₃) δ 3.4-4.2 ppm (m, 4, C₃ -H), 4.6 (m, 1, C₃₁ -H) 5.55 (broad s,1, NH) 6.8-7.7 (m, 7, aromatic H).

EXAMPLE 238-Chloro-6-(2-fluorophenyl)-2,3,3a,4-tetrahydro-1H-imidazo[1,5-a][1,4]benzodiazepine-1-thione

To a solution of 15.0 g. (49.5 mmol) of2-aminomethyl-7-chloro-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepinein 200 ml. of methylene chloride, cooled in a dry ice-acetone bath, wasadded a solution of 9.2 g (80 mmol) of thiophosgene n 15 ml. ofmethylene chloride followed by 16.0 g (160 mmol) of triethylamine. After10 minutes the bath was removed and the mixture allowed to warm to roomtemperature with stirring. After an additional 5 min, 200 ml ofsaturated aqueous sodium bicarbonate was added, stirred 15 min, andfiltered to give the crude product. The organic layer from the filtratewas removed, dried with anhydrous sodium sulfate and evaporated in vacuoto give additional product. An analytical sample was obtained byrecrystallization from methylene chloride-petroleum ether, mp 233°-237°;Ir (KBr) 1580 and 1460 cm⁻¹ ; nmr (DMSO-d₆) 3.40-4.30 δ (m, 4H),4.60-5.30 (m, 1H) and 7.00-8.50 (m, 8H); uv λ max 227 nm (ε=25830),infl. 277 (4400), infl. 318 (1064).

Anal. Calcd. for C₁₇ H₁₃ ClFN₃ S: C, 59.05; H, 3.79; N, 12.15 Found: C,58.97; H, 3.69; N, 12.02.

EXAMPLE 248Chloro-3a,4-dihydro-6-(2-fluorophenyl)-1-methylthio-3H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 8.3 g (24 mmol) of end product of Example 23 and 4.8 ml ofdimethyl sulfate in 300 ml of ethanol was heated on a steam bath for 30min, cooled, evaporated in vacuo and treated with 50 ml 2N sodiumhydroxide and warmed for a few minutes. The mixture was diluted withwater, extracted with methylene chloride, dried with anhydrous sodiumsulfate, evaporated in vacuo and the residue treated with ether to givethe crude product. Recrystallization from methylene chloride ether gavea white powder, mp 163°-165°: Ir (KBr) 1580 and 1480 cm⁻¹ ; nmr (CDCl₃)2.40 (s, 3H), 3.40-4.30 (m, 4H), 4.60-5.00 (m, 1H) and 6.80-7.60 (m,aromatic, 7H); uv λ max infl. 240 nm (ε=11800) and infl. 280 (3400);mass spectrum m/e 359 (M⁺).

Anal. Calcd. for C₁₈ H₁₅ ClFN₃ S: C, 60.08; H, 4.70; N, 11.68. Found: C,60.22; H, 4.17; N, 11.85.

EXAMPLE 258-Chloro-6-(2-fluorophenyl)-1-methylthio-4H-imidazo[1,5a][1,4]benzodiazepine

A mixture of 2.8 g (7.8 mmol) of the end product of Example 24 and 13 gof activated manganese dioxide in 500 ml of toluene was refluxedovernight. The mixture was filtered through Celite, evaporated in vacuoand the residue treated with ether-petroleum ether to give a tan solid.Recrystallization from methylene chloride-ether gave a white powder, mp180°-181°; Ir (KBr) 1610 and 1480 cm⁻¹ ; nmr (CDCl₃) 2.60 δ (s, 3H),4.10 (d, J=12Hz, 1H) 5.20 (d, J=12Hz, 1H) and 6.90-7.80 (m, aromatic,8H); uv λ max 219 nm (ε=36500), infl. 242 (19900) and 270 (8700); massspectrum m/e 357 (M⁺).

Anal. Calcd. for C₁₈ H₁₃ ClFN₃ S: C, 60.42; H, 3.66; N, 11.74. Found: C,60.32; H, 3.43; N, 12.00.

EXAMPLE 268-Chloro-6-(2-fluorophenyl)-1-methylsulfinyl-4H-imidazo[1,5-a][1,4]benzodiazepine

A solution of 450 mg (1.25 mmol) of the end product of Example 25 in 10ml of acetic acid and 1 ml of 30% hydrogen peroxide was allowed to standat room temperature overnight. The solution was treated with ice andammonium hydroxide; the resulting solid was collected, washed withwater, dissolved in methylene chloride, treated with anhydrous sodiumsulfate and charcoal, filtered and evaporated in vacuo to a white foam,mp 95°-110°: Ir (KBr) 1610, 1480 and 1047 cm⁻¹ ; nmr (CDCl₃) 2.95 (s,3H), 4.15 (d, J=13Hz, 1H), 5.25 (d, J=13Hz, 1H), 6.95-8.40 (m, aromatic,8H); uv λ max 219 nm (ε=37500), infl. 243 (20000); sh. 265 (13700),infl. 305 (1200); mass spectrum m/e 373 (M⁺).

Anal. Calcd. for C₁₈ H₁₃ ClFN₃ OS: C, 57.83; H, 3.50; N, 11.24. Found:C, 57.61; H, 3.54; N, 11.17.

EXAMPLE 278-Chloro-6-(2-fluorophenyl)-1-methylsulfonyl-4H-imidazo[1,5-a][1,4]benzodiazepine-5-oxide

A solution of 2.0 g (5.57 mmol) of the end product of Example 25 in 40ml of acetic acid and 9 ml of 30% hydrogen peroxide was heated on asteam bath for 45 min. The solution was diluted with water andneutralized with ammonium hydroxide. The resulting solid was washed withwater, triturated with methanol and washed with ether to give a whitefoam which was recrystallized from methylene chloride-petroleum etherand then methylene chloride-methanol to give white prisms, mp 219°-220°:Ir (KBr) 1326 and 1137 cm⁻¹ ; nmr (DMSO-d₆) 3.30 δ (s, 3H), 5.10 (s,broad, 2H), 6.90-7.90 (m, aromatic, 8H); uv λ max 217 nm (ε=25500),infl. 235 (22850), sh. 270 (14800), 300 (10200); mass spectrum m/e 405(M⁺).

Anal. Calcd. for C₁₈ H₁₃ ClFN₃ O₃ S: C, 53.27; H, 3.23 Found: C, 53.46;H, 3.30.

EXAMPLE 28

    ______________________________________                                        Capsule Formulation                                                                            mg/capsule                                                   ______________________________________                                        8-Chloro-6-(2-chlorophenyl)-                                                                   1.0     5.0     10.0  40.0                                   1-thiomethyl-4H-imidazo-                                                      [1,5-a][1,4]                                                                  benzodiazepin-3-carboxamide                                                   Lactose          149.0   182.5   215.0 260.0                                  Cornstarch       40.0    50.0    60.0  80.0                                   Magnesium Stearate                                                                             2.0     2.5     3.0   4.0                                    Talc             8.0     10.0    12.0  16.0                                   Total            200 mg  250 mg  300 mg                                                                              400 mg                                 ______________________________________                                    

Procedure

(1) Mix Items 1-3 in a suitable mixer. Mill through suitable mill.

(2) Mix with Items 4 and 5 and fill on capsule machine.

EXAMPLE 29

    ______________________________________                                        Capsule Formulation                                                                            mg/capsule                                                   ______________________________________                                        8-Chloro-6-(2-chlorophenyl)-                                                                   1.0     5.0     10.0   40.0                                  1-thiomethyl-4H-imidazo-                                                      [1,5-a][1,4]                                                                  benzodiazepin-3-carboxamide                                                   Lactose, Anhydrous DTG                                                                         127.0   142.5   182.0 216.0                                  Microcrystalline Cellulose                                                                     40.0    50.0    60.0  80.0                                   Modified Starch  10.0    12.5    15.0  20.0                                   Cornstarch       20.0    25.0    30.0  40.0                                   Magnesium Stearate                                                                             2.0     2.5     3.0   4.0                                    Total            200 mg  250 mg  300 mg                                                                              400 mg                                 ______________________________________                                    

Procedure

(1) Mix Items 1-5 in a suitable mixer for 1 to 15 minutes.

(2) Add Item 6 and mix for 5 minutes. Compress on a suitable press.

EXAMPLE 30

    ______________________________________                                        Capsule Formulation                                                                            mg/capsule                                                   ______________________________________                                        8-Chloro-6-(2-chlorophenyl)-                                                                   1.0     5.0     10.0  40.0                                   1-thiomethyl-4H-imidazo-                                                      [1,5-a][1,4]                                                                  benzodiazepin-3-carboxamide                                                   Lactose          195.0   230.0   264.0 273.0                                  Pregelatinized Starch                                                                          12.5    15.0    17.5  20.0                                   Cornstarch       25.0    30.0    35.0  40.0                                   Modified Starch  12.5    15.0    17.5  20.0                                   Magnesium Stearate                                                                             4.0     5.0     6.0   7.0                                    Total            250 mg  300 mg  350 mg                                                                              400 mg                                 ______________________________________                                    

Procedure

(1) Mix Items 1-5 in a suitable mixer, granulate with water. Dryovernight in an oven. Mill through a Fitzpatrick mill.

(2) Mix with Item 6 and compress on a suitable press.

EXAMPLE 31

The compound8-Chloro-6-(2-chlorophenyl)-1-methoxy-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid methyl ester can be formulated by following the Examples of 28-30.

EXAMPLE 32

The compound8-Chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylicacid, methyl ester, ethanolate can be formulated by following theExamples of 28-30.

We claim:
 1. A compound of the formula ##STR8## wherein R₁ is hydrogen,halogen or trifluoromethyl, R₂ is selected from the group consisting oflower alkylthio together with the sulfoxide and sulfone thereof, halo,lower alkylamino or lower alkoxy; R₃ is selected from the groupconsisting of hydrogen, --COOR₄ wherein R₄ is hydrogen or lower alkyl,--CONR₆ R₅ wherein R₅ and R₆ are hydrogen or lower alkyl; and X ishydrogen or halogen and the pharmaceutically acceptable salts andN-oxides thereof.
 2. A compound of the formula ##STR9## wherein X ishydrogen, chloro or fluoro; R₂ is --O alkyl, chloro, --S alkyl or NHCH₃; R₃ is --CONH₂, ##STR10##